The present invention relates to a new and useful process for the treatment of human cognitive disorders by administering a metabolic enhancer such as piracetam in combination with a cholinergic precursor such as lecithin.
It has been estimated that at least 10% of persons over the age of 60 will eventually suffer severe mental deterioration. A much larger number will experience sufficient cognitive decline to impede their activities. At the other end of the spectrum, more than half of the residents in nursing homes in the United States have been classified as senile. Prior to the present invention, it has been generally concluded that there is no currently available treatment for age-related cognitive deterioration. Apparently the lack of an effective treatment is due to a lack of understanding of the underlying etiology of cognitive decline. Reisberg, B.; Ferris, S. and Gershon, S. "Psychopharmacological Aspects of Cognitive Research in the Elderly: Some current perspectives." In: INTERDISCIPLINARY TOPICS OR GERONTOLOGY, W. Meir-Ruge and H. von Hahn (eds.), S. Karger, Basel 15:132-152, 1979 (copy enclosed). In particular, several current treatments based upon the hypothesis of cerebral arteriosclerotic etiology had not been shown to be of any value. Reisberg et al., op. cit., p. 133. Examples of these unsuccessful attempts are treatment with cerebral vasodilators to increase blood flow and treatment with hyperbaric oxygen to increase cerebral oxygen supply. Treatments with psychoactive drugs for the modification of behavioral symptoms have had no effect upon cognitive performance.
Substances related to the present invention have been considered individually in connection with human senility but heretofore not been demonstrated to act synergistically in combination upon humans in a positive clinically significant manner.
U.S. Pat. No. 3,459,738 disclosed the synthesis of the compound 2-oxy-pyrrolidone acetamine (piracetam) for its marked effect upon the involuntary rythmical oscillation of the eyeballs known as nystagmus. It is a nootropic derivative of gamma-aminobutyric acid capable of crossing the blood-brain barrier.
The effects of piracetam on both human and animal subjects has been studied. In elderly patients, piracetam has had no significant positive effect on the cognitive state of those severely impaired by senile dementia (e.g., those who had to be accompanied for out-patient treatment or who were unable to function is society) (Reisberg, op cit., 137-138). On elderly patients with mild or moderate cognitive decline piracetam has had some positive effect in short term therapeutic trials (up to twelve weeks), although not proved to be of definite value in reversing or even slowing the progressive memory or other cognitive deficit which sometimes occurs with aging. See, e.g., Stegink, A. J., "The clinical use of Piracetam, a new nootropic drug: The treatment of symptoms of senile involution", Argn. Forsch (Drug Research), 22/6:975-977, 1972; Stegink, A. J. and Tjeerdsma, H., "Piracetam: Controlled study in a group of patients with cerebral arteriosclerosis", DE73G181. UCB-Pharmaceutical Division, DRDM-Clinical Development, Brussels, Belgium.
There has been some very recent work indicating that piracetam does improve visual memory in patients with mild to moderate senile dementia, Alzheimer's type (SDAT). Again, this work does not indicate an effectiveness for piracetam that is suitable for clinical treatment. (Branconnier, R. J., and Cole, J. O., "Final report of a clinical trail of the efficacy and safety of piracetam in the amelioration of the neuropsychological symptoms associated with mild primary degenerative dementia", unpublished manuscript, dated Apr. 22, 1980.).
The primary effectiveness noted for piracetam, aside from its effect upon nystagmus has been in treating persons of various ages for the symptoms of alcohol withdrawal, sickle cell anaemia, vertigo and in improving recovery after brain surgery.
U.S. Pat. No. 4,221,784 disclosed the process of administering lecithin to increase acetylcholine levels in the brain to alleviate the effects of tardive dykinesia, manic-depressive disease, memory impairment or familial ataxis. This disclosure was based on only one example involving just one patient who had suffered memory loss and whose memory quotient by the Wechsler Memory and Intelligence test increased from 122 to 140 after 6 weeks of lecithin ingestion. This result does not claim nor suggest may clinical effectiveness of lecithin for the treatment of senile dementia.
The interest of the present inventors in acetylcholine levels derives from the hypothesis that memory function may be related to interneuronal synaptic events and activities. One of the major known neurotransmitter systems of the brain believed to play a role in age-associated cognitive decline is the cholinergic, which is affected by acetylcholine. The cholinergic system of the brain has been shown to be strongly related to memory functioning. However, any simple direct connection between reducing memory impairment and increasing acetylcholine levels in moderately impaired outpatients has not been demonstrated. For example, deanol, which presumed to increase brain acetylcholine was given in a 4-week open trail to 14 such patients and produced no changes in memory. Ferris, S. H., Sathananthan, G., Gershon, S. and Clark, C. "Senile dementia. Treatment with Deanol." J. Am. Geriat. Soc., 25:241-44 (1977). Similarly, an open, dose-ranging study using up to 20 g/day of choline chloride, a cholinergic precursor and direct cholinergic agonist, gave no consistent improvement in cognitive test performance. Ferris, S. H.; Sathananthan, G.; Reisberg, B. and Gershon, S. "Long Term Choline Treatment of Memory Impaired Elderly Patients", Science 205, 1039-40, 1979.
In summary, although both a choline/lecithin treatment or a piracetam treatment may produce some small cognitive effects in senile dementia patients, neither therapy is of clinically significant value, at least with treatment durations of up to three months.
Choline and piracetam has been administered in combination to rats. This improved the rats' performance in one-trail passive avoidance procedure over their performance when receiving only choline or piracetam. Bartus, R. T., "Pharmacological manipulations of age-related neurobehavioral dysfunctions." Paper presented at the 10th Annual National Meeting of the American Aging Association, Oct. 2-4, 1980, Houston, Texas.
Prior to the present invention autopsy studies on humans lead to reclassification of senile dementia into "Senile dementia, Alzheimer's type (SDAT)", or "multi-infarct dementia (MID)", or senile dementia secondary to mixed causes, including both SDAT and MID. SDAT is now thought to account for more than 50% of all cases of senile dementia. Alzheimer's disease (i.e., SDAT) is only know to occur in humans, thereby limiting the significance of etiological analogies from animal studies.
Alzheimer's disease is defined neuropathologically as the presence of neurofibrillary tangles (NFT's) together with senile plaques. The NFT's of the Alzheimer's type are only known to occur in human beings, furthermore, the association of NFT's with senile plaques is a uniquely human phenomenon. Hence, Alzheimer's disease is only known to occur in human beings, thereby limiting the significance of animal analogies. Thus, prior to the present invention, it was not known that the major cause of human senile dementia would respond with clinically significant positive results to the process of the present invention or that the combination of clinically insufficient therapies would co-act synergistically in human patients to provide a significant clinical therapy.